Left ventricular remodeling that occurs following an ischemic episode such as an acute myocardial infarction, or subsequent to other damage to the myocardium, can lead to heart failure, which is a leading cause of morbidity and mortality in many parts of the world.
Granulocyte macrophage colony stimulating factor (GM-CSF) is a pro-inflammatory cytokine that may play a role in the process of blood vessel formation in patients with coronary artery disease (Seiler et al., Circulation 104:2012-2017, 2001). It has been suggested that GM-CSF induces neovascularization in the heart (see, e.g., U.S. Patent Application Publication No. 20050233992) However, the role of GM-CSF in cardiac re-modeling is unclear. Physical training in patients with congestive heart failure can reduce serum levels of GM-CSF while increasing exercise tolerance (Adamopoulos, et al., Eur. Heart J. 22:791-797, 2001). Further, in a rat model of left ventricular remodeling, treatment with romurtide, which induces GM-CSF, caused expansion of the damaged area (Maekawa et al., J. Amer. Coll. Cardiol. 44:1510-1520, 2004). GM-CSF receptor has also been detected on cardiomycoytes from end-stage heart failure patients (Postiglione et al., Eur. J. Heart Failure 8:564-570, 2006).
This invention is based, in part, on the discovery that neutralization of GM-CSF reduces cardiac damage that results from ischemia, e.g., acute myocardial infarction, and improves ventricular function.